The E7 genes of the anogenital associated HPVs encode multi-functional proteins that are structurally and functionally related to the adenovirus E1A proteins (Ad E1A) and the simian virus 40 large tumor antigen (SV40 TAg). The E7 proteins encoded by the high risk HPVs differ from those encoded by the low risk HPVs in a number of biochemical and biological properties, most notably in their in vitro transformation potential. The high risk HPV E7 proteins efficiently cooperate with the ras oncoprotein to transform baby rat kidney cells and together with E6 are necessary for the efficient immortalization of primary human epithelial cells. HPV E7 proteins form complexes with pRB and an intact pRB binding site in E7 is required for the transformation of baby rat kidney cells in cooperation with ras. The differences in transformation efficiencies of the high risk and the low risk HPV encoded E7 proteins closely correlates with their respective pRB binding efficiencies. Both low risk and high risk HPV E7 proteins efficiently transactivate the Ad E2 promoter. Similar to the 12S form of Ad E1A, HPV E7 requires a functional pRB binding site and intact target E2F binding sites in the Ad E2 promoter for transactivation of this promoter. Moreover, HPV E7, like 12S Ad E1A and SV40 TAg, is able to disrupt heteromolecular complexes of the cellular transcription factor E2F. The ability of E7 to disrupt this transcription factor complex correlates with the different pRB binding efficiencies of the high risk and the low risk HPV encoded E7 proteins. The pRB binding site is the sole determinant for the observed differences. Peptides consisting of the pRB binding site of E7, however, were not able to disrupt the pRB/E2F complex, suggesting that additional carboxy terminal sequences in E7 are also required for the efficient disruption of the pRB/E2F complex and that E7 and E2F may interact with non-identical sites of pRB.